CN103865964A - Method for synthesizing (R)-3-amino-piperidine by adopting transaminase method - Google Patents
Method for synthesizing (R)-3-amino-piperidine by adopting transaminase method Download PDFInfo
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Abstract
The invention provides a method for synthesizing (R)-3-amino-piperidine (I) by adopting a transaminase method. The method comprises the following steps: transforming nitrogen-protected 3-piperidone into nitrogen-protected (R)-3-amino-piperidine by transaminase reaction under existence of an amino donor and transaminase; then removing a protecting group of the nitrogen-protected (R)-3-amino-piperidine to obtain (R)-3-amino-piperidine or a salt thereof, wherein the protecting group is C1-4 alkoxycarbonyl, carbobenzoxy or benzyl. The method is ingenious in design, concise and efficient in synthetic route, simple and feasible in technological process, green and environment-friendly, a novel method is provided for large-scale industrial production of (R)-3-amino-piperidine, and the method is applicable to large-scale popularization and application.
Description
Technical field
The present invention relates to (R)-3-amino piperidine synthesis technical field, more specifically, relate to (R)-3-amino piperidine enzyme process synthesis technical field, refer to especially the method for synthetic (the R)-3-amino piperidine of a kind of transaminase method.
Background technology
(R)-3-amino piperidine (I) is a kind of important medicine intermediate, be mainly used to synthetic dipeptidyl peptidase-IV (DPP-IV) inhibitor, as hypoglycemic drugs such as Egelieting (Alogliptin), BI 1356s (Linagliptin).Up to now, the document of synthetic (the R)-3-amino piperidine (I) of report is more.
In PCT public announcement of a patent application text WO2007075630 and WO2008028654, taking 3-aminopyridine as starting raw material, obtain (R)-3-amino piperidine dihydrochloride through catalyzed oxidation, fractionation and salify, as shown in synthetic route A.
Synthetic route A:
Although this method route is succinct, the catalytic hydrogenation of pyridine will be used more expensive catalyzer and higher pressure, not too convenient concerning industrial production; And split the isomer of having wasted half, not only make production cost increase at double, and cause discarded isomer discharge.
Document (Adv.Synth.Catal.2008; 350 (6); 807-812) report is taking niacinamide as raw material; by catalytic hydrogenation, amido Boc protection, Hoffmann degraded, fractionation and de-Boc protection, salify five step reactions obtain (R)-3-amino piperidine dihydrochloride.Although raw material niacinamide is easy to get than 3-aminopyridine, the problem that this route faces the same with synthetic route A substantially, does not have tangible progress, and reacts loaded down with trivial details, and step is many.
In PCT public announcement of a patent application text WO2008102720, racemic N-benzyl-3-piperidyl urea splits by enzyme and obtains (R)-N-benzyl-3-piperidyl urea, through hofmann rearrangement, the de-benzyl of hydrogenation, salify obtains (R)-3-amino piperidine dihydrochloride, as shown in synthetic route B.
Synthetic route B:
Although this route has adopted enzyme fractionation, but still can produce the discarded isomer of half, not only make production cost increase at double, and cause discarded isomer discharge; In addition, raw material N-benzyl-3-piperidyl urea is also not easy to obtain, and has further increased production cost; And react loaded down with trivial details, step is many, is unfavorable for suitability for industrialized production.
In Chinese patent application CN101565397, taking ethyl nipecotate as starting raw material, by amido protect, ammonia solution, Hoffmann degraded, fractionation, Deprotection salify obtain (R)-3-amino piperidine dihydrochloride.Although ethyl nipecotate by protecting on nitrogen-atoms, split more effective than 3-amino piperidine resolution through transaminase again, but basic reaction process and synthetic route B are more or less the same, exist equally raw material ethyl nipecotate to be not easy to obtain, increase production cost; And react loaded down with trivial details, step is many, be unfavorable for the problem of suitability for industrialized production.
Document (Bioorgan.Med.Chem.2006,14 (12); 4158-4181.) report, taking D-Orn hydrochloride as raw material, under the condition of-78～-45 DEG C, react with thionyl chloride, obtain (R)-3-amino piperidine-2-ketone crude product by strongly basic anion exchange resin (AmberliteIRA-400) again, after purifying, obtain (R)-3-amino piperidine with Lithium Aluminium Hydride reduction, and after hydrochloric acid reaction, become hydrochloride.As shown in synthetic route C.
Synthetic route C:
Although this method need not split, but D-Orn is on the high side, and reaction process is to carry out under cold condition, and synthesizes its intermediate product by strongly basic anion exchange resin, also to use Lithium Aluminium Hydride to make reductive agent, all increase industrial production cost; And react loaded down with trivial details, step is many, is unfavorable for suitability for industrialized production.
In Chinese patent application CN201210290868.0, mention the method for asymmetric synthesis of a kind of (R)-3-amino piperidine (I), as shown in synthetic route D.By 3-piperidone compound and Chiral Amine (R)-1-phenylethylamine generation dehydration reaction of protection; first obtain chirality enamine compound; hydrogenation under the catalysis of Raney's nickel or palladium carbon again; obtain chiral amine compound; finally remove chiral auxiliary and the amino protecting group of methylbenzylamine, thereby obtained (R)-3-amino piperidine (I).
Synthetic route D:
Although this method is applicable to suitability for industrialized production, use chiral auxiliary (R)-1-phenylethylamine, slightly almost, reaction process is slightly loaded down with trivial details for Atom economy, nor can obtain the intermediate after hydrogenation with 100% de value.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings for above existence; the method of synthetic (the R)-3-amino piperidine of a kind of transaminase method is provided; the method design is ingenious; synthetic route is succinctly efficient; technical process is simple; environmental protection, produces (R)-3-amino piperidine (I) for industrial scale new method is provided, and is suitable for large-scale promotion application.
To achieve these goals, the invention provides the method for synthetic (the R)-3-amino piperidine (I) of a kind of transaminase method, be characterized in, pass through transamination reaction, under amino donor and transaminase existence, the 3-piperidone (III) of nitrogen protection is converted into (R)-3-amino piperidine (II) of nitrogen protection; Then (R)-3-amino piperidine (II) of nitrogen protection is sloughed protecting group and is obtained (R)-3-amino piperidine (I) or its salt,
Wherein, protecting group PG is C
1-4carbalkoxy, carbobenzoxy-(Cbz) or benzyl.
Preferably, described amino donor is Isopropylamine.Described amino donor can also be other common amino donor, such as phenylethylamine, D-alanine etc.
Preferably, described transaminase is ω-transaminase.Described transaminase can also be non-ω-transaminase.
More preferably, described ω-transaminase has the aminoacid sequence shown in SEQ ID NO:1.
Preferably, the solvent of described transamination reaction is mixed solvent or the water of water and organic solvent.
More preferably, described organic solvent is methyl-sulphoxide or tetrahydrofuran (THF).
Preferably, the pH value of described transamination reaction is 8.0～9.5.
Preferably, the temperature of described transamination reaction is 25～50 DEG C.
Preferably, described C
1-4carbalkoxy is ethoxycarbonyl or tertbutyloxycarbonyl.
Preferably, described salt is hydrochloride or hydrobromate.
Preferably, if PG is tertbutyloxycarbonyl, deprotection base in the alcoholic solution of hydrochloric acid; If PG is ethoxycarbonyl, in aqueous hydrochloric acid or potassium hydroxide aqueous solution, heat deprotection base; If PG is carbobenzoxy-(Cbz) or benzyl, deprotection base under the condition of Pd/C hydrogenation.
Beneficial effect of the present invention is specifically:
1, the method for synthetic (the R)-3-amino piperidine (I) of transaminase method of the present invention is passed through transamination reaction, under amino donor and transaminase existence, the 3-piperidone (III) of nitrogen protection is converted into (R)-3-amino piperidine (II) of nitrogen protection; Then (R)-3-amino piperidine (II) of nitrogen protection is sloughed protecting group and is obtained (R)-3-amino piperidine (I) or its salt, and wherein protecting group is C
1-4carbalkoxy, carbobenzoxy-(Cbz) or benzyl, design ingeniously, and synthetic route is succinctly efficient; technical process is simple; environmental protection, produces (R)-3-amino piperidine (I) for industrial scale new method is provided, and is suitable for large-scale promotion application.
2, the transaminase of the method for synthetic (the R)-3-amino piperidine (I) of transaminase method of the present invention is ω-transaminase, there is the aminoacid sequence shown in SEQ ID NO:1, the key index such as transformation efficiency, reaction system concentration that largely improves reaction, makes the method be applicable to suitability for industrialized production.
3, the method for synthetic (the R)-3-amino piperidine (I) of transaminase method of the present invention only needs two-step reaction the 3-piperidone (III) of nitrogen protection can be converted into (R)-3-amino piperidine (I); the ee value that obtains product is greater than 90%; generally in 99% left and right; yield is also higher, is suitable for large-scale promotion application.
Embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment.Should be understood that following specific embodiment is only for the present invention is described, instead of limitation of the present invention.
Embodiment 1:
The intestinal bacteria optimal codon gene order SEQ ID NO:2 of full gene composite coding SEQ ID NO:1 sequence, and at gene two ends design limit restriction enzyme site NdeI and BamHI, be subcloned into carrier pET24a(Novagen company) corresponding site, obtain recombinant plasmid transformed e. coli bl21 (DE3), the recombination bacillus coli that obtains expressing ω-transaminase.
Full gene synthesizes and subclone all entrusts Nanjing Genscript Biotechnology Co., Ltd. to complete.
The fermentation process of expressing recombination bacillus coli is as follows:
Substratum compound method: LB substratum (peptone 10g/L, yeast extract 5g/L, sodium-chlor 10g/L, pH7.2); TB substratum (peptone 12g/L, yeast extract 24g/L, glycerine 5g/L, KH
2pO
42.13g/L, K
2hPO
43H
2o16.43g/L, pH7.0～7.5); 121 DEG C of autoclave sterilizations 20 minutes.
Fermentation culture conditions: the bacterial classification building is inoculated into containing in the LB liquid nutrient medium of 100 μ g/mL kantlex, after 37 DEG C, 220rpm overnight incubation, be inoculated into (containing 100 μ g/mL kantlex) in fresh TB substratum by 1% inoculum size, 37 DEG C, 220rpm are cultured to OD600=5～6, adding final concentration is IPTG(sec.-propyl-β-D-thio-galactose pyran-glucoside of 0.2mM), induce at 28 DEG C and spend the night.Fermented liquid is in 8000rpm, and 10min is centrifugal, removes supernatant, obtains thalline for subsequent use in-20 DEG C of preservations.
Bacterial cell disruption liquid acquisition methods: the water resuspension of 4 times of volumes for the centrifugal acquisition thalline of fermented liquid, then ultrasonication.
The preparation of enzyme lyophilized powder: bacterial cell disruption liquid 12000rpm, 20min is centrifugal, and supernatant lyophilize obtains enzyme lyophilized powder.
Embodiment 2:
1, the preparation of (R)-N-tertbutyloxycarbonyl-3-amino piperidine (2-2)
Isopropylamine 100g is dissolved in 100mL water, under lasting ice-water bath condition, regulate pH to 8.5 with aqueous hydrochloric acid, and add methyl-sulphoxide 70mL, then use 0.1M, the Tris-HCl damping fluid of pH=8.5 is diluted to 700mL and is preheated to 45 DEG C, add again the dimethyl sulfoxide solution 200mL that contains N-Boc-3-piperidone (2-1) 50g, finally add ω-transaminase lyophilized powder 1g and PLP(phosphoric acid Vitamin B6) 0.8g, react the Isopropylamine control pH=8.5 with 20%, under temperature 45 C, transform 24h, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, dry, concentrated white solid (R)-N-tertbutyloxycarbonyl-3-amino piperidine (2-2) 43.1g, yield 85.7%, the ee%=99.3% of obtaining of organic phase after merging.
1H?NMR(400MHz,CDCl
3)δ4.02–3.78(m,2H),3.82(m,2H),3.61(m,1H),1.92(m,1H),1.72(m,1H),1.61–1.42(s,12H),1.32(m,1H);MS(ESI)m/z=201(M
++1).
2, the preparation of (R)-N-tertbutyloxycarbonyl-3-amino piperidine (2-2)
Isopropylamine 100g is dissolved in 100mL water, under lasting ice-water bath condition, regulate pH to 9.5 with aqueous hydrochloric acid, then use 0.1M, the Tris-HCl damping fluid of pH=9.5 is diluted to 800mL and temperature is adjusted to 25 DEG C, add again and contain N-Boc-3-piperidone (2-1) 50g, finally add ω-transaminase lyophilized powder 1g and PLP(phosphoric acid Vitamin B6) 0.8g, reacts the Isopropylamine control pH=9.5 with 20%, at 25 DEG C of temperature, transform 48h, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, dry, concentrated white solid (R)-N-tertbutyloxycarbonyl-3-amino piperidine (2-2) 40.7g, yield 81.8%, the ee%=98.9% of obtaining of organic phase after merging.Spectral data is shown in embodiment 2-1.
3, the preparation of (R)-3-amino piperidine dihydrochloride (2-3)
(R)-N-Boc-3-amino piperidine (2-2) 54g is joined to 300mL, in the HCl-ethanolic soln of 2mol/L, stirred overnight at room temperature.Reaction finishes, and has solid to separate out, and filters, a small amount of washing with alcohol, and vacuum-drying obtains white solid (R)-3-amino piperidine dihydrochloride (2-3) 43.1g, yield: 92.4%.
1H?NMR(400MHz,DMSO)δ9.62(s,2H),8.65(s,3H),3.43(d,J=11.3Hz,2H),3.18(d,J=12.2Hz,1H),2.90(t,J=11.2Hz,1H),2.76(t,J=11.7Hz,1H),2.05(d,J=11.7Hz,1H),1.87(d,J=12.1Hz,1H),1.74(d,J=11.9Hz,1H),1.61(d,J=11.3Hz,1H).MS(ESI)m/z=101(M
++1).
Embodiment 3:
1, the preparation of (R)-N-benzyl-3-amino piperidine (3-2)
Isopropylamine 100g is dissolved in 100mL water, under lasting ice-water bath condition, regulate pH to 8.0 with aqueous hydrochloric acid, and add tetrahydrofuran (THF) 80mL, then use 0.1M, the Tris-HCl damping fluid of pH=8.0 is diluted to 700mL and is preheated to 50 DEG C, add again the tetrahydrofuran solution 200mL that contains N-benzyl-3-piperidone (3-1) 50g, finally add ω-transaminase lyophilized powder 1g and PLP(phosphoric acid Vitamin B6) 0.8g, react the Isopropylamine control pH=8.0 with 20%, under temperature 50 C, transform 18h, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, dry, concentrated colorless oil (R)-N-benzyl-3-amino piperidine (3-2) 45.2g, yield 90.9%, the ee%=99.0% of obtaining of organic phase after merging.
1H?NMR(400MHz,CDCl
3)δ7.21–7.30(m,5H),3.49(d,J=13.2Hz,1H),3.45(d,J=13.2Hz,1H),2.91(m,1H),2.72(d,J=9.6Hz,1H),2.63(s,2H),2.56(m,1H),2.08(m,1H),1.94(m,1H),1.80(m,1H),1.68(m,1H),1.53(m,1H),1.17(m,1H);MS(ESI)m/z=191(M
++1).
2, the preparation of (R)-3-amino piperidine two hydrobromates (3-3)
(R)-N-benzyl-3-amino piperidine (3-2) 45.0g and Pd/C4.5g are joined in the solution of 400mL acetic acid to 30 kilograms of pressure room temperature reactions 24 hours.Reaction finishes, and filters with being lined with diatomaceous sand core funnel, is spin-dried for filtrate, obtains light yellow viscous liquid.Again yellow thick liquid is dissolved in to 50mL dehydrated alcohol, and drips Hydrogen bromide/ethanolic soln formation hydrobromate, leach the solid of separating out, use a small amount of washing with alcohol, vacuum-drying obtains white solid two hydrobromates (3-3) 57.6g, yield: 93.3%.
1H?NMR(400MHz,DMSO)δ9.62(s,2H),8.65(s,3H),3.43(d,J=11.3Hz,2H),3.18(d,J=12.2Hz,1H),2.90(t,J=11.2Hz,1H),2.76(t,J=11.7Hz,1H),2.05(d,J=11.7Hz,1H),1.87(d,J=12.1Hz,1H),1.74(d,J=11.9Hz,1H),1.61(d,J=11.3Hz,1H).MS(ESI)m/z=101(M
++1).
Embodiment 4:
1, the preparation of (R)-N-ethoxycarbonyl-3-amino piperidine (4-2)
Isopropylamine 100g is dissolved in 100mL water, under lasting ice-water bath condition, regulate pH to 9.0 with aqueous hydrochloric acid, then use 0.1M, the Tris-HCl damping fluid of pH=9.0 is diluted to 700mL and is preheated to 45 DEG C, add again and contain N-ethoxycarbonyl-3-piperidone (4-1) 50g, finally add ω-transaminase lyophilized powder 1g and PLP(phosphoric acid Vitamin B6) 0.8g, reacts the Isopropylamine control pH=9.0 with 20%, under temperature 45 C, transform 24h, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, dry, concentrated oily matter (R)-N-ethoxycarbonyl-3-amino piperidine (4-2) 44.1g, yield 87.6%, the ee%=99.7% of obtaining of organic phase after merging.
1H?NMR(400MHz,CDCl
3)δ4.14(t,J=6.9Hz,2H),4.08–3.83(m,2H),3.85(m,2H),3.64(m,1H),1.94(m,1H),1.73(m,1H),1.53(m,1H),1.33(m,1H),1.22(t,J=7.0Hz,3H);MS(ESI)m/z=173(M
++1).
2, the preparation of (R)-3-amino piperidine dihydrochloride (2-3)
(R)-N-ethoxycarbonyl-3-amino piperidine (4-2) 44g is joined in 300mL concentrated hydrochloric acid (37%) to reflux 18h.Reaction finishes, and by concentrated the aqueous solution dry, then uses washing with alcohol, vacuum-drying to obtain white solid (R)-3-amino piperidine dihydrochloride (2-3) 40.3g, yield: 91.1%.Spectral data is shown in embodiment 2-3.
3, the preparation of (R)-3-amino piperidine (4-3)
(R)-N-ethoxycarbonyl-3-amino piperidine (4-2) 35g is joined to 100mL, in 40% potassium hydroxide solution, reflux 24h.Reaction finishes, and adds in hydrochloric acid and unnecessary alkali, and the aqueous solution is concentrated, removes by filter most of salt, and mother liquor underpressure distillation, obtains white solid (R)-3-amino piperidine (4-3) 18.4g, yield: 89.3%.
1H?NMR(400MHz,DMSO)δ3.42(d,J=11.3Hz,2H),3.15(d,J=12.2Hz,1H),2.87(t,J=11.2Hz,1H),2.73(t,J=11.7Hz,1H),2.02(d,J=11.7Hz,1H),1.84(d,J=12.1Hz,1H),1.71(d,J=11.9Hz,1H),1.60(d,J=11.3Hz,1H).MS(ESI)m/z=101(M
++1).
Embodiment 5:
1, the preparation of (R)-N-carbobenzoxy-(Cbz)-3-amino piperidine (5-2)
Isopropylamine 10g is dissolved in 10mL water, under lasting ice-water bath condition, regulate pH to 8.0 with aqueous hydrochloric acid, and add tetrahydrofuran (THF) 80mL, then use 0.1M, the Tris-HCl damping fluid of pH=9.0 is diluted to 70mL and is preheated to 30 DEG C, add again the tetrahydrofuran solution 20mL that contains N-carbobenzoxy-(Cbz)-3-piperidone (5-1) 5.0g, finally add ω-transaminase lyophilized powder 0.1g and PLP(phosphoric acid Vitamin B6) 0.08g, react the Isopropylamine control pH=8.0 with 20%, at 30 DEG C of temperature, transform 40h, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, dry, concentrated colorless oil (R)-N-carbobenzoxy-(Cbz)-3-amino piperidine (5-2) 4.5g, yield 90.4%, the ee%=99.7% of obtaining of organic phase after merging.
1H?NMR(400MHz,DMSO)δ7.41–7.25(m,5H),5.08(s,2H),3.95–3.78(m,2H),3.22(bs,2H),2.82–2.75(m,1H),2.61–2.45(m,2H),1.82–1.78(m,1H),1.69–1.59(m,1H),1.40–1.33(m,1H),1.22–1.10(m,1H);MS(ESI)m/z=235(M
++1).
2, the preparation of (R)-3-amino piperidine two hydrobromates (2-3)
(R)-N-benzyl-3-amino piperidine (5-2) 4.5g and Pd/C0.5g are joined in the solution of 40mL acetic acid to 20 kilograms of pressure room temperature reactions 12 hours.Reaction finishes, and filters with being lined with diatomaceous sand core funnel, is spin-dried for filtrate, obtains light yellow viscous liquid.Again yellow thick liquid is dissolved in to 10mL dehydrated alcohol, and drips hydrochloric acid/ethanolic soln formation hydrobromate, leach the solid of separating out, use a small amount of washing with alcohol, vacuum-drying obtains white solid dihydrochloride (2-3) 3.2g, yield: 95.6%.Spectral data is shown in embodiment 2-3.
The 3-piperidone (III) that the method for synthetic (the R)-3-amino piperidine (I) of transaminase of the present invention is protected taking nitrogen is as raw material; by transaminase effect; the 3-amino piperidine intermediate (II) that obtains the nitrogen protection of R configuration, then intermediate (II) is sloughed protecting group and is obtained (R)-3-amino piperidine (I) or its acceptable salt under suitable condition.Synthetic route is succinctly efficient.Only need two-step reaction the 3-piperidone (III) of nitrogen protection can be converted into (R)-3-amino piperidine (I), the ee value that obtains product is greater than 90%, and generally in 99% left and right, yield is also higher.
ω-transaminase that the method for synthetic (the R)-3-amino piperidine (I) of transaminase of the present invention adopts has the aminoacid sequence shown in SEQ ID NO:1, and transformation efficiency is higher, is mainly reflected in and transforms concentration and transformation efficiency aspect.Document ChemBioChem2008, several transaminases that adopt in 9,363-365, transformation efficiency only has 20～40%, transforms concentration lower; And ω-transaminase transformation efficiency in employing the present invention is brought up to more than 99%, transform concentration and be significantly improved.
In the present invention, technical process is simple, environmental protection.The present invention is with synthetic (the R)-3-amino piperidine (I) of transaminase method, mainly taking water as solvent, and reaction conditions gentleness, no waste discharge, environmentally friendly, be applicable to suitability for industrialized production.
Therefore, synthetic route of the present invention is succinctly efficient, and technical process is simple, and environmental protection is produced (R)-3-amino piperidine (I) for industrial scale new method is provided.
In sum; the method design of synthetic (the R)-3-amino piperidine of transaminase method of the present invention is ingenious; synthetic route is succinctly efficient; technical process is simple; environmental protection; produce (R)-3-amino piperidine (I) for industrial scale new method is provided, be suitable for large-scale promotion application.
In this specification sheets, the present invention is described with reference to its specific embodiment.But, still can make various amendments and conversion obviously and not deviate from the spirit and scope of the present invention.Therefore, specification sheets is regarded in an illustrative, rather than a restrictive.
Claims (10)
1. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method, it is characterized in that, pass through transamination reaction, under amino donor and transaminase existence, the 3-piperidone (III) of nitrogen protection is converted into (R)-3-amino piperidine (II) of nitrogen protection; Then (R)-3-amino piperidine (II) of nitrogen protection is sloughed protecting group and is obtained (R)-3-amino piperidine (I) or its salt,
Wherein, PG is C
1-4carbalkoxy, carbobenzoxy-(Cbz) or benzyl.
2. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that, described amino donor is Isopropylamine.
3. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that, described transaminase is ω-transaminase.
4. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 3, is characterized in that, described ω-transaminase has the aminoacid sequence shown in SEQ ID NO:1.
5. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that, the solvent of described transamination reaction is mixed solvent or the water of water and organic solvent.
6. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 5, is characterized in that, described organic solvent is methyl-sulphoxide or tetrahydrofuran (THF).
7. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that, the pH value of described transamination reaction is 8.0～9.5.
8. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that, the temperature of described transamination reaction is 25～50 DEG C.
9. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that described C
1-4carbalkoxy is ethoxycarbonyl or tertbutyloxycarbonyl.
10. the method for synthetic (the R)-3-amino piperidine (I) of transaminase method according to claim 1, is characterized in that, described salt is hydrochloride or hydrobromate.
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| CN104178536A (en) * | 2014-07-31 | 2014-12-03 | 洛阳华荣生物技术有限公司 | Biological preparation method for R-3-aminopiperidine |
| CN105130879A (en) * | 2015-07-24 | 2015-12-09 | 沧州那瑞化学科技有限公司 | Preparation method of (R)-3-Boc-aminopiperidine |
| CN105734089A (en) * | 2014-12-11 | 2016-07-06 | 南京博优康远生物医药科技有限公司 | An asymmetric synthesis method for (R)-3-amino piperidine derivatives |
| CN106520719A (en) * | 2016-11-25 | 2017-03-22 | 华东理工大学 | S-shaped omega-transaminase ATA-W12 as well as gene and application thereof |
| CN107604019A (en) * | 2017-09-27 | 2018-01-19 | 上海合全药物研发有限公司 | The method that living things catalysis prepares the amino piperidine of (R) 1 N benzene methoxycarbonyl group 3 |
| CN107604020A (en) * | 2017-09-27 | 2018-01-19 | 上海合全药物研发有限公司 | The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 |
| CN114235972A (en) * | 2021-10-28 | 2022-03-25 | 乳源东阳光药业有限公司 | Method for determining linagliptin impurity RBP-1 content |
| CN114277008A (en) * | 2020-09-28 | 2022-04-05 | 弈柯莱生物科技(上海)股份有限公司 | (R) -selective transaminase and application thereof |
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| CN104178536A (en) * | 2014-07-31 | 2014-12-03 | 洛阳华荣生物技术有限公司 | Biological preparation method for R-3-aminopiperidine |
| CN104178536B (en) * | 2014-07-31 | 2017-04-19 | 洛阳华荣生物技术有限公司 | Biological preparation method for R-3-aminopiperidine |
| CN105734089A (en) * | 2014-12-11 | 2016-07-06 | 南京博优康远生物医药科技有限公司 | An asymmetric synthesis method for (R)-3-amino piperidine derivatives |
| CN105130879A (en) * | 2015-07-24 | 2015-12-09 | 沧州那瑞化学科技有限公司 | Preparation method of (R)-3-Boc-aminopiperidine |
| CN106520719A (en) * | 2016-11-25 | 2017-03-22 | 华东理工大学 | S-shaped omega-transaminase ATA-W12 as well as gene and application thereof |
| CN106520719B (en) * | 2016-11-25 | 2019-06-07 | 华东理工大学 | A kind of ω of S type-transaminase ATA-W12 and its gene and application |
| CN107604019A (en) * | 2017-09-27 | 2018-01-19 | 上海合全药物研发有限公司 | The method that living things catalysis prepares the amino piperidine of (R) 1 N benzene methoxycarbonyl group 3 |
| CN107604020A (en) * | 2017-09-27 | 2018-01-19 | 上海合全药物研发有限公司 | The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 |
| CN114277008A (en) * | 2020-09-28 | 2022-04-05 | 弈柯莱生物科技(上海)股份有限公司 | (R) -selective transaminase and application thereof |
| CN114277008B (en) * | 2020-09-28 | 2024-09-24 | 弈柯莱生物科技(集团)股份有限公司 | (R) -selective transaminase and application thereof |
| CN114235972A (en) * | 2021-10-28 | 2022-03-25 | 乳源东阳光药业有限公司 | Method for determining linagliptin impurity RBP-1 content |
| CN114235972B (en) * | 2021-10-28 | 2023-08-22 | 乳源东阳光药业有限公司 | Method for determining content of linagliptin impurity RBP-1 |
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